Today, in the western world about one couple out of five is sub-fertile. Sub-fertility is defined as a failure to conceive after 1 year of unprotected sexual intercourse. In about half of all sub-fertile couples, male sub-fertility is observed, and in almost 40% of such couples the sub-fertility is solely due to male factors.
Male fertility status is evaluated by a semen analysis. The most common analysis, known as “routine semen analysis”, provides information on the number of spermatozoa present in the ejaculate, the proportion of motile (and/or progressively motile) sperm cells and the percentage of cells that are morphologically normal. Male sub-fertility is usually associated with one or more of low sperm production (oligozoospermia), poor sperm motility (asthenozoospermia) and abnormal sperm morphology (teratozoospermia). The combination of all three of these defects (“oligoasthenoteratozoospermia”, OTA) is the most common cause of male sub-fertility. The probability of conception increases with increased sperm concentration, motility and normal morphology. The World Health Organization (WHO) has proposed guidelines specifying threshold values for these parameters for classifying semen samples as normal or abnormal (10).
Routine semen analysis, however, has many limitations resulting in a significant proportion of patients exhibiting unexplained sub-fertility. To refine the diagnosis, additional tests have been developed that provide more information on the fertilization potential of human semen. These tests include various sperm cell functional tests (11), functional morphology tests as the “motile sperm organelle morphology examination” (MSOME, 12) and tests examining the extent of DNA damage in sperm cells, for example, the sperm chromatin structure assay (SCSA, 11).
In some cases, the cause of male sub-fertility is known. These include varicocele, hormonal disorders, infections, immunological infertility, obstructions of the male genital tract and cryptorchidism. Current medical and surgical therapies are available for these conditions (1). However in a large number of cases of male sub-fertility, the cause is not known. In these cases, various treatments may be applied to sub-fertile men, often on an ad hoc basis. These treatments include antiestrogens, aromatase inhibitors, androgens, FSH, pentoxyphylline, arginine, carnitine, glutathione, vitamins (A, C and E), and oligominerals (zinc, selenium) (1).
When a treatment of male infertility does not lead to a pregnancy after a reasonable period of time or if the diagnostic measures show that no improvement in fertility status is possible, then assisted reproduction techniques (ART) may be considered. The various assisted reproduction procedures enhance the sperm fertilization potential by bypassing some or all migration barriers of the lower and upper female genital tract as well as the ovum investments. ART procedures that are common today include intrauterine insemination (IUI, 2, 3), classic in vitro fertilization (IVF, 4, 5) and IVF-Intracytoplasmic sperm injection (IVF-ICSI, 6). An improvement in ICSI is a technique known as “intracytoplasmic morphologically selected injection” (IMSI, 7-9) in which the fine morphology of motile spermatozoa is examined by high power microscopy and the spermatozoa exhibiting the best morphology of the nuclei are selected for ICSI.
Sperm cells from a variety of species have been shown In vitro to bind and take up exogenous DNA (13). DNA binding is mediated at least in part by CD4 and MHCII molecules present on the surface of sperm cells and is antagonized by the glycoprotein IF-1, present in the seminal fluid. Sperm interaction with extracellular cell free DNA activates intracellular nucleases such as DNase that cleave the sperm genomic DNA, eventually leading to a cell death process which resembles apoptosis.
Bovine DNase I has been used clinically since 1965. It is used in the former Soviet countries to treat infections caused by DNA viruses such as Herpes and adenovirus. It is believed that DNase degrades the viral DNA to mono and oligo nucleotides. This medication is usually used to treat Herpes simplex type 2 (genital herpes) infections, Herpetic eye infections caused by Herpes simplex, Herpes zoster infections, inflammation of the respiratory track as bronchitis and pneumonia and tuberculosis. For these applications it is administered either by intramuscular injections, inhalation or as eye drops. Recombinant human DNase I is another clinically used DNase I. It is an FDA approved medicine administrated by inhalation to treat cystic fibrosis (CF) patients. In these patients retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbation of infections. Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes that accumulate in response to infection. DNase I hydrolyzes the DNA in sputum of CF patients and reduces sputum viscoelasticity (14).